Details

Autor(en) / Beteiligte

• Zhang, An‐liu
• Tang, Shun‐fang
• Yang, Yue
• Li, Chang‐zhe
• Ding, Xue‐jiao
• Zhao, Hua
• Wang, Jun‐hua
• Yang, Guang‐hong
• Li, Jun

Titel

Histone demethylase JHDM2A regulates H3K9 dimethylation in response to arsenic‐induced DNA damage and repair in normal human liver cells

Ist Teil von

• Journal of applied toxicology, 2020-12, Vol.40 (12), p.1661-1672

Ort / Verlag

England: Wiley Subscription Services, Inc

Erscheinungsjahr

2020

Link zum Volltext

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• Long‐term arsenic exposure is a worldwide public health problem that causes serious harm to human health. The liver is the main target organ of arsenic toxicity; arsenic induces disruption of the DNA damage repair pathway, but its mechanisms remain unclear. In recent years, studies have found that epigenetic mechanisms play an important role in arsenic‐induced lesions. In this study, we conducted experiments in vitro using normal human liver cells (L‐02) to explore the mechanism by which the histone demethylase JHDM2A regulates H3K9 dimethylation (me2) in response to arsenic‐induced DNA damage. Our results indicated that arsenic exposure upregulated the expression of JHDM2A, downregulated global H3K9me2 modification levels, increased the H3K9me2 levels at the promoters of base excision repair (BER) genes (N‐methylpurine‐DNA glycosylase [MPG], XRCC1 and poly(ADP‐ribose)polymerase 1) and inhibited their expression levels, causing DNA damage in cells. In addition, we studied the effects of overexpression and inhibition of JHDM2A and found that JHDM2A can participate in the molecular mechanism of arsenic‐induced DNA damage via the BER pathway, which may not be involved in the BER process because H3K9me2 levels at the promoter region of the BER genes were unchanged following JHDM2A interference. These results suggest a potential mechanism by which JHDM2A can regulate the MPG and XRCC1 genes in the process of responding to DNA damage induced by arsenic exposure and can participate in the process of DNA damage repair, which provides a scientific basis for understanding the epigenetic mechanisms and treatments for endemic arsenic poisoning. Arsenic poisoning can lead to abnormal DNA damage and repair, which is related to the regulation of histone methylation. JHDM2A is the histone demethylase that specifically removes the methyl group from histone lysine H3K9, which is overexpressed in various tumors. After inhibition of JHDM2A, it can increase the expression of H3K9me2 and inhibit the proliferation of cancer cells. Our study shows that arsenic can upregulate JHDM2A and aggravate DNA damage, and JHDM2A inhibition can reduce levels of DNA damage.